On the Use of Hierarchical Probabilistic Models for Characterizing and Managing Uncertainty in Risk/Safety Assessment

A general probabilistically-based approach is proposed for both cancer and noncancer risk/safety assessments. The familiar framework of the original ADI/RfD formulation is used, substituting in the numerator a benchmark dose derived from a hierarchical pharmacokinetic/pharmacodynamic model and in the denominator a unitary uncertainty factor derived from a hierarchical animal/average human/sensitive human model. The empirical probability distributions of the numerator and denominator can be combined to produce an empirical human-equivalent distribution for an animal-derived benchmark dose in external-exposure units.